Oral dosage forms account for approximately eighty percent of all the drug dosage forms on the market. Oral dosage forms are non-invasive, easily administered and have high patient compliance.
Orally administered therapeutic agents are rapidly transported to the stomach and small intestine for absorption across the gastrointestinal (GI) mucosal membranes into the blood. The efficiency of absorption of a drug following oral administration can be low because of metabolism within the GI tract and first-pass metabolism within the liver resulting in relatively lengthy onset times or erratic absorption characteristics that are not well suited to control acute disorders. The majority of oral dosage forms on the market are designed for GI delivery. Relatively few oral dosage forms are designed for delivery through the oral mucosa.
However, oral transmucosal delivery offers a number of advantages in that it can provide a shorter onset time and more consistent time (Tmax) to maximal plasma concentration (Cmax) than oral delivery in particular for lipophilic drugs. This is because the drug rapidly passes directly and efficiently through the relatively permeable epithelium of the highly vascularized mucosal tissue to the plasma, thus rapidly reaching the circulation while avoiding the slower, often inefficient and variable GI uptake. In addition, due to the avoidance of the first-pass metabolism and avoidance of inefficient drug absorption though the gut, sublingual drug uptake also improves drug bioavailability. It is therefore advantageous for a drug to be delivered through the mucus membranes of the oral cavity, (e.g., via the sublingual route), when rapid onset, consistent Tmax and Cmax are advantageous.
In carrying out oral transmucosal drug delivery, the drug is absorbed through the epithelial membranes of the oral cavity. However, frequently the key risk associated with oral transmucosal delivery is the enhanced potential for swallowing the medication owing to the continuous generation, backward flow and swallowing of the saliva. This becomes a particular risk when the used dosage forms are large, thereby producing increased saliva response, which, in turn, leads to increased swallowing and removal of the dosage form from the oral mucosa. The present invention provides the advantage that the formulations have bioadhesive properties which facilitate adherence to the oral mucosa during administration, thus minimizing the risk of ingestion and inefficient delivery potential.
Various solid dosage forms, such as sublingual tablets, troches, lozenges, lozenges-on-a-stick, chewing gums, and buccal patches, have been used to deliver drugs via the oral mucosal tissue. Solid dosage forms such as lozenges and tablets are commonly used for oral transmucosal delivery of drugs, e.g., nitroglycerin sublingual tablets.
Relevant formulations and delivery systems for oral or buccal administration of pain medication have been previously disclosed, for example, in: U.S. Pat. Nos. 2,698,822; 3,972,995; 3,870,790; 3,444,858; 3,632,743; 4,020,558; 4,229,447; 4,671,953; 4,836,737; and 5,785,989.
Relevant non-patent publications that discuss buccal and sublingual administration of drugs include: Culling et al., in the Br. J. Clin. Pharm. 17, 125-131, 1984, disclosing the sublingual administration of the glyceryl trinitrate; Osborne et al., published in the Clin. Pharmac. Ther. 47, 12-19, 1990, on buccal administration of morphine; Rosen et al., published in the Am. J. Drug Alcohol Abuse, 19, 451-464, 1993, on the sublingual administration of buprenorphine.
U.S. Patent Publication No. 20020160043 discloses compositions and methods of manufacture for dissolvable and non-dissolvable drug-containing dosage-forms for noninvasive administration of medications through mucosal tissues of the mouth, pharynx, and esophagus of a patient.
U.S. Pat. Nos. 4,671,953 and 5,785,989 (Stanley, et al.) disclose a lozenge-on-a-stick dosage form for transmucosal drug delivery. Once the appropriate amount of drug is delivered, the patient or caregiver can remove the lozenge, thus, stopping the drug delivery to prevent overdose.
U.S. Pat. No. 5,296,234 (Hadaway, et al.) discloses a stick-like holder and packaging, including a tamper resistant foil pouch, for a hardened, sucrose based matrix containing a dosage of fentanyl citrate affixed to one end of the holder and a flange to prevent swallowing of the holder when placed in a patient's mouth to medicate or pre-medicate the patient.
U.S. Pat. Nos. 6,974,590, 6,764,696, 6,641,838, 6,585,997, 6,509,036, 6,391,335, 6,350,470, 6,200,604 and US Patent Publication Nos. 20050176790, 20050142197 and 20050142198 describe pharmaceutical combinations of active compounds such as fentanyl and congeners thereof in combination with an effervescent agent used as penetration enhancer to influence the permeability of the active compound across the buccal, sublingual, and gingival mucosa.
U.S. Pat. No. 6,761,910 and U.S. Patent Publication No. 20040213855 disclose pharmaceutical compositions for the treatment of acute disorders by sublingual administration of an essentially water-free, ordered mixture of microparticles with at least one pharmaceutically active agent adhered to the surfaces of the carrier particles by way of a bioadhesion and/or mucoadhesion promoting agent.
U.S. Pat. No. 6,759,059 discloses compositions and methods for the treatment of acute pain by sublingual administration of compositions which contain from 0.05 to 20 mg fentanyl or a pharmaceutically acceptable salt thereof in the form of microparticles which are adhered to the surface of carrier particles by way of a bioadhesion and/or mucoadhesion promoting agent, wherein each tablet is approximately 100 mg in size.
U.S. Pat. No. 5,800,832 and U.S. Pat. No. 6,159,498 (Tapolsky, et al.), and U.S. Patent Publication Nos. 20030194420 and 20050013845 disclose a water soluble, biodegradable drug delivery device, e.g., a bilayer film disk having an adhesive layer and a backing layer, both water-soluble, which adheres to mucosal surfaces.
U.S. Pat. Nos. 6,682,716; 6,855,310; 7,070,762 and 7,070,764 and (Rabinowitz, et al.), disclose delivery of an analgesic via the inhalation route using a method which comprises: a) heating a thin layer of analgesic drug on a solid support to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles.
U.S. Pat. No. 6,252,981 (Zhang et al.) discloses oral mucosal drug delivery as an alternative method of systemic drug delivery formulation and method for oral transmucosal delivery of a pharmaceutical. The invention provides a drug formulation comprising a solid pharmaceutical agent in solid solution with a dissolution agent in solid form, yielding a solid solution. The solid solution formulation may be further combined with buffers and other excipients as needed in order to facilitate the drug's manufacturing, storage, administration and delivery through oral mucosal tissue. The formulation can be used with a variety of oral transmucosal delivery dosage forms, such as a tablet, lozenge, lozenge on a stick, chewing gum, and buccal or mucosal patch. See, also Zhang et al, Clin Pharmacokinet. 2002; 41(9):661-80.
Although various oral mucosal drug delivery systems have been described, there remains a need for improved formulations for use in an oral transmucosal dosage form that allows for controlled drug delivery of the dosage form, ability to manipulate and control the drug dissolution kinetics and thereby enable a number of pharmacokinetic profiles. The present invention addresses this problem.